In breast cancer, specific aspects of the malignant phenotype can be maintained by the interaction of growth factors with their receptors. During the last funding period, we have shown that the insulin-like growth factors (IGFs) stimulate breast cancer cell proliferation, motility, adhesion, and survival. Distinct signaling pathways have been identified that correlate with specific phenotypes. In addition, interruption of the type I IGF receptor (IGF1R) inhibits IGF action in breast cancer cells. We hypothesize that activation of IGF1R regulates specific signal transduction pathways that result in several aspect of the malignant phenotype. These findings have two important implications for breast cancer. First, by understanding the key signaling pathways regulated by IGF1R, we can better target the molecules required for the malignant behavior of breast cancer cells. Second, anti-IGF strategies need to be developed to test their therapeutic potential in the treatment of breast cancer. In this application, we propose three specific aims: 1) to determine if IRS-1 and its downstream signaling pathways are required for IGF-stimulated proliferation in breast cancer cells; 2) to determine if IRS-2 and its downstream signaling pathways are required for breast cancer cell adhesion and migration; and 3) to inhibit IGF effects in vivo with a chimeric monoclonal antibody directed against the type I IGF receptor. By performing these studies we will provide further evidence that the IGFs play a critical role in breast cancer and that targeting of the IGF1R is a feasible therapeutic strategy for treatment of this disease. [unreadable] [unreadable]